1. The Parkinson’s disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4
- Author
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Wolfgang Wurst, Thomas Ott, Kathrin Brockmann, Daniela Vogt-Weisenhorn, Andrea Wenninger-Weinzierl, Marita Munz, Ralf Kühn, Saskia Biskup, Florian Giesert, Natalja Funk, and Thomas Gasser
- Subjects
0301 basic medicine ,Cancer Research ,drug effects [Neuronal Outgrowth] ,metabolism [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] ,lcsh:Medicine ,pharmacology [Fibroblast Growth Factors] ,Mice ,0302 clinical medicine ,cytology [Fibroblasts] ,Insulin ,Phosphorylation ,lcsh:Science ,pharmacology [Insulin] ,Glucose Transporter Type 4 ,Multidisciplinary ,Kinase ,Parkinson Disease ,LRRK2 ,metabolism [rab GTP-Binding Proteins] ,Cell biology ,ddc ,Intracellular signal transduction ,metabolism [Proto-Oncogene Proteins c-akt] ,Signal transduction ,Technology Platforms ,metabolism [Fibroblasts] ,Signal Transduction ,drug effects [Signal Transduction] ,Cell Survival ,drug effects [Cell Survival] ,Neuronal Outgrowth ,metabolism [Parkinson Disease] ,Biology ,Leucine-rich repeat ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Animals ,Humans ,Protein kinase B ,lcsh:R ,Fibroblasts ,metabolism [Glucose Transporter Type 4] ,pathology [Parkinson Disease] ,Rats ,nervous system diseases ,Fibroblast Growth Factors ,030104 developmental biology ,rab GTP-Binding Proteins ,biology.protein ,genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] ,lcsh:Q ,Proto-Oncogene Proteins c-akt ,ddc:600 ,030217 neurology & neurosurgery ,GLUT4 - Abstract
Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson’s disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson’s patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications.
- Published
- 2019
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